The nuclear receptor transcription factor PPAR? is an established target for FDA approved drugs for patients with type II diabetes mellitus (T2DM). These drugs and numerous other known ligands that bind PPAR? increase insulin sensitivity T2DM patients. Most of the PPAR?-binding drugs also display adverse side effects, including increased risk of bone fractures, weight gain, and heart disease. Despite these negative indications, PPAR? remains an important T2DM therapeutic target. Detailed understanding of how ligands affect PPAR? activity may facilitate the development of new drugs with fewer adverse effects. The transcription of PPAR? target genes is affected, in part, by small molecule ligands that bind to its ligand-binding domain (LBD) and change the interaction between PPAR? and coregulator proteins (corepressors and coactivators). In the inactive transcriptionally repressive form, PPAR? is bound to corepressor proteins. Binding of an agonist ligand, including FDA approved drugs that target PPAR?, causes a conformational change that releases corepressors and allows binding of coactivators; this generally results in an increase the expression of PPAR? target genes. While many crystal structures have been reported for PPAR? bound to coactivator peptides and agonist ligands, no structural data has been reported for PPAR? bound to a corepressor. Agonist ligands stabilize the activation function-2 (AF-2) surface, decreasing binding affinity for corepressors while increasing affinity for coactivators. The stabilized AF-2 surface with coactivators likely explains the numerous PPAR? crystal structures bound to coactivator peptides. However, our preliminary data show that a dynamic AF-2 surface, which samples multiple conformations, facilitates corepressor binding. The dynamics of the AF-2 surface when bound to a corepressor may explain why no crystal structure of PPAR? bound to a corepressor has been reported, since the dynamic surface could inhibit crystal formation. Using a multidisciplinary approach combining NMR, biochemical, biophysical and cell- based functional methods we seek to report the first structural understanding of how corepressor proteins bind PPAR?. The connection of PPAR? corepressor binding to functional effects could aid in the design of novel compounds targeting PPAR? with lower unwanted side effects profiles.